WO1990000401A2 - Inhibiteurs de protease neutre stimulant l'innervation de fibres musculaires - Google Patents
Inhibiteurs de protease neutre stimulant l'innervation de fibres musculaires Download PDFInfo
- Publication number
- WO1990000401A2 WO1990000401A2 PCT/GB1989/000878 GB8900878W WO9000401A2 WO 1990000401 A2 WO1990000401 A2 WO 1990000401A2 GB 8900878 W GB8900878 W GB 8900878W WO 9000401 A2 WO9000401 A2 WO 9000401A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- inhibitor
- muscle
- canp
- alkyl
- innervation
- Prior art date
Links
- 230000030214 innervation Effects 0.000 title claims abstract description 20
- 210000001087 myotubule Anatomy 0.000 title claims abstract description 14
- 230000001737 promoting effect Effects 0.000 title claims abstract description 11
- 108090000145 Bacillolysin Proteins 0.000 title 1
- 102000035092 Neutral proteases Human genes 0.000 title 1
- 108091005507 Neutral proteases Proteins 0.000 title 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title 1
- 239000003112 inhibitor Substances 0.000 claims abstract description 48
- 210000003205 muscle Anatomy 0.000 claims abstract description 29
- 102000007590 Calpain Human genes 0.000 claims abstract description 28
- 108010032088 Calpain Proteins 0.000 claims abstract description 28
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 108010052968 leupeptin Proteins 0.000 claims abstract description 25
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 20
- 210000000225 synapse Anatomy 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 12
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- -1 2-methyl-prop-l-yl Chemical group 0.000 claims description 4
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 229920000768 polyamine Polymers 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- 150000005693 branched-chain amino acids Chemical class 0.000 claims description 3
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- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
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- BMGMINKVTPDDRZ-UHFFFAOYSA-N 2-acetamido-n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide;n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methyl-2-(propanoylamino)pentanamide Chemical compound CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N.CCC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N BMGMINKVTPDDRZ-UHFFFAOYSA-N 0.000 description 4
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- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
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- 241001480052 Aspergillus japonicus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
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- 102000005927 Cysteine Proteases Human genes 0.000 description 1
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
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- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical group NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 1
- 230000010442 axonal sprouting Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
Definitions
- OF MUSCLE FIBERS This invention relates to a novel therapeutic method for promoting innervation of muscle fibers, particularly reinnervation of muscle fibers following nerve trauma due, for example, to injury or disease.
- the invention further relates to pharmaceutical preparations (including implantable devices) for use in carrying out the aforementioned method.
- CIP Calcium activated neutral protease
- mammalian muscle fibers are innervated by more than one axon (known as polyneuronal innervation) .
- polyneuronal innervation axon
- CANP enzymes are involved in the elimination of the excess innervation.
- the remaining single mature nerve ending continues to change its terminal branching pattern by gradually becoming more complex, a process termed "synapse remodelling".
- Calcium activated neutral proteases have also been considered to be involved in this reorganisation of mature mammalian neuromuscular junctions.
- an inhibitor of calcium activated neutral protease in the manufacture of a pharmaceutical composition or device for use in promoting synapse formation and innervation of muscle fibers, particularly synapse formation and reinnervation of muscle fibres following nerve trauma.
- a method of promoting synapse formation and innervation of muscle fibers, particularly synapse formation and reinnervation of muscle fibers following nerve trauma which comprises administering an inhibitor of calcium activated neutral protease (CANP) so as to provide an effective concentration of said inhibitor to the at least partially dennervated area of a muscle.
- an inhibitor of calcium activated neutral protease (CANP) so as to provide an effective concentration of said inhibitor to the at least partially dennervated area of a muscle.
- the inhibitor of calcium activated neutral protease (CANP) used in the present invention is preferably an oligopeptide comprising at least one amino acid residue.
- oligopeptide refers to a molecule containing a residue of an amino acid HN_ ⁇ C00H linked via at least one peptide bond (-C0.NH-) to another amino acid or to an amine.
- the or each amino acid is preferably an amino acid of normal metabolism.
- the inhibitor is of low-toxicity, is non-immunogenic and is able to penetrate cell membranes and enter nerve terminals.
- a class of peptide inhibitors which have been found to be particularly effective comprises peptides which contain one or more branched chain amino acid residues and optionally one or more residues of basic amino acids or amines.
- the branched chain amino acid residues are preferably selected from valine, leucine and isoleucine.
- the N-terminus of said oligopeptide is blocked, for example by an acyl group derived from a C. _,- carboxylic acid.
- suitable acyl groups include acyl groups derived from acetyl, propionyl, cis- or trans-oxiranedicarboxylic acid or a C 1 _i, alkyl half-ester of cis- or trans-oxiranedicarboxylic acid.
- the oligopeptide comprises at least one residue derived from an aliphatic polyamine containing 1 to 6 carbon atoms, preferably an aliphatic polyamine residue having the structure
- R. and R_ may be the same or different and represent hydrogen, C, j . alkyl or, C. alkoxy and wherein individual groups (CR_R_) may be the same or different, R represents H, NH 2 , OH, C00H, C00R' , CHO, COROR", CH_0H, CH DR' , C ⁇ alkyl, guanidyl or amino-(C. alkyl), wherein each of R' and R" independently represents C, n alkyl and m is an integer from 1 to 4.
- re e w invention are represented by the formula
- R 1 , R_ and R, and m are as defined above,
- R ⁇ is an acyl group derived from acetyl, propionyl, cis- or trans-oxiranedicarboxylic acid or a
- R_ is prop-2-yl, 2-methyl-proD-l-yl or 1-methvl-prop-l-yl. 0
- the group -NH-(CR R_) R_ preferably has one of the following structures ⁇ *
- E64 an epoxy compound which was originally isolated from Aspergillus japonicus.
- the structure of E64 is shown below.
- E64c a derivative of E6 wherein the agmatine residue is replaced by an N-isopropyl (ethylene diamine) residue.
- the structure of E64c is shown below.
- leupeptins a class of oligopeptides which have been isolated f om various species of Actinomycetes.
- One compound in the class is itself known as leupeptin and has the structure N-acetyl-L-leucyl-Lleucyl-L-arginal, i.e.
- the pharmaceutical preparation ma3 r be in the form of an injectable solution comprising the inhibitor together with a suitable excipient, for example sterile, pyrogen free water or isotonic saline.
- a suitable excipient for example sterile, pyrogen free water or isotonic saline.
- the quantity of CANP inhibitor administered should be sufficient to provided a concentration in the
- extracellular fluid 10 to 5 x 10 J g/ml of CANP inhibitor.
- the quantity administered should provide a concentration of 10 to 10 ⁇ g/ml.
- the pharmaceutical preparation may be in the form of an implantable device from which the inhibitor is released.
- the device preferably comprises a polymer matrix which acts as a non-toxic carrier which releases the inhibitor over a period of time.
- the implantable device may comprise a silicone rubber strip containing the inhibitor and can, for example, be formed by mixing the inhibitor in powdered form with a rubber solution and allowing the mixture to set.
- the " amount of inhibitor used and the size of the implant will depend on the extent of nerve trauma.
- the device may be implanted onto the surface of the muscle adjacent the denervated region.
- the inhibitor penetrates cell membranes and enters nerve terminals and thus inhibits calcium activated neutral protease at these locations. As a result this inhibition the reinnervation of muscle fibres and synapse formation is promoted.
- the implant strips were prepared by mixing predetermined amounts of the test compound (in powder form) with a calculated quantity of rubber solution (Dow Corning 3 ⁇ 0) and allowing the mixture to set overnight. When dry, small strips (about 3 nun x 1 mm x 0.5 mm, weighing 1-1.5 mg) were cut from the resulting flexible strips of rubber.
- the test compounds in each 1 mg strip were as follows:
- the maximum tetanic tension was measured for the operated muscles and expressed as a percentage of the contralateral muscle tension.
- the mean motor unit size (a parameter indicative of degree of recovery from nerve trauma) was estimated from the oscilloscope traces of twitch tension recordings from the soleus muscle. The number of motor units in each operated and contralateral muscle was determined. This was achieved by gradually increasing the stimulus intensity to the motor nerve, and recording stepwise increments in twitch tension, due to the successive recruitment of individual motor units, by stimulating axons with different thresholds. This was continued until a plateau was reached when all the motor axons were recruited and the tension could not be increased further. The average motor unit size was then found by dividing the number of motor units found in the operated muscle into the maximum tetanic tension (g) for that muscle. This value can then be expressed as a percentage of the mean size of a motor unit from the contralateral muscle, obtained by the same method.
- Sections of the operated and contralateral soleus muscles stained using the combined Ag/Acetylcholine esterase method showed that the total amount of axonal sprouting in the leupeptin treated and control groups was very low.
- a group of rats (weigh 27 ⁇ 39 g) aged 17-19 days (an age which is after the elimination of polyneural innervation) were partially denervated and one day later the test (leupeptin) and control (leucine/arginine) strips were implanted as described in Example 1.
- Leupeptin 89..' Thus, as in the younger group of rats in Example 1, leupeptin increased the recovery of the operated muscle tension compared to the control group. The maximum tentanic tension at 2 months for the leupeptin operated muscle was very similar to the results obtained at 2 weeks which suggests that the improvement, caused by treatment with leupeptin is permanent.
- Example 1 the leupeptin treated operated muscles showed a 3-fold increase of mean motor unit size compared to their contralateral muscles which was greater than that shown by the control partially denervated soleus muscles.
- Leupeptin was found to have no significant effect on maximum tetanic tension, mean motor unit size or the pattern of innervation.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Procédé stimulant la formation de synapses et l'innervaton (et notamment la réinnervation) de fibres musculaires, consistant à administer un inhibiteur de protéase neutre activée par le calcium (CANP) pour obtenir une concentration efficace dudit inhibiteur dans la zone d'un muscle au moins partiellement dépourvue de terminaisons nerveuses. On décrit également des préparations destinées à être utilisées par ce procédé.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8815962.9 | 1988-07-05 | ||
| GB888815962A GB8815962D0 (en) | 1988-07-05 | 1988-07-05 | Pharmaceutical preparation & method for promoting reinnervation of muscle fibers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1990000401A2 true WO1990000401A2 (fr) | 1990-01-25 |
| WO1990000401A3 WO1990000401A3 (fr) | 1990-03-22 |
Family
ID=10639884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1989/000878 WO1990000401A2 (fr) | 1988-07-05 | 1989-07-04 | Inhibiteurs de protease neutre stimulant l'innervation de fibres musculaires |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB8815962D0 (fr) |
| WO (1) | WO1990000401A2 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992021373A1 (fr) * | 1991-06-03 | 1992-12-10 | Logothetou Rella Helen | Utilisation d'inhibiteurs de proteases neutres activees par le calcium dans des preparations pharmaceutiques |
| WO1998038990A1 (fr) * | 1997-03-07 | 1998-09-11 | Hoechst Marion Roussel, Inc. | Methode de traitement d'un trauma associe a des lesions du cerveau, de la moelle epiniere ou de nerfs peripheriques au moyen de carbobenzyloxy phenylalaninals di- et tri-pepetidiques n-proteges |
| FR2778851A1 (fr) * | 1998-05-19 | 1999-11-26 | Aetsrn | Composition a base d'inhibiteurs de cysteine-proteases pour retarder la senescence, l'autodestruction et l'hemolyse des erythrocytes |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100673A2 (fr) * | 1982-08-02 | 1984-02-15 | The Research Foundation Of State University Of New York | Méthode pour favoriser la régénération des fibres nerveuses |
-
1988
- 1988-07-05 GB GB888815962A patent/GB8815962D0/en active Pending
-
1989
- 1989-07-04 WO PCT/GB1989/000878 patent/WO1990000401A2/fr unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100673A2 (fr) * | 1982-08-02 | 1984-02-15 | The Research Foundation Of State University Of New York | Méthode pour favoriser la régénération des fibres nerveuses |
Non-Patent Citations (4)
| Title |
|---|
| Developmental Brain Research, Vol. 28, 1986, Elsevier Science Publishers B.V. (Biomedical Division), A.L. CONNOLD et al.: "Effect of Low Calcium and Protease Inhibitors on Synapse Elimination During Postnatal Development in Ther at Soleus Muscle", pages 99-107, see the whole article * |
| Developmental Brain Research, Vol. 33, 1987, Elsevier Science Publishers B.V. (Biomedical Division), G.J. SWANSON et al.: "Effects of Low Calcium and Inhibition of Calciumactivated Neutral Protease (CANP) on Mature Nerve Terminal Structure in the Rat Sternocostalis Muscle", pages 199-203 see the whole article * |
| Experimental Neurology, Vol. 91, 1986, Academic Press Inc., K. KOMATSU et al.: "Beneficial Effect of New Thiol Protease Inhibitors, Epoxide Derivatives, on Dystrophic Mice", pages 23-29 * |
| Proc. Natl. Acad. Sci. USA, Vol. 78, No. 12, December 1981, J. HOLLENBERG SHER et al.:"Successful Treatment of Murine Muscular Dystrophy with the Proteinase inhibitor Leupeptin", pages 7742-7744 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992021373A1 (fr) * | 1991-06-03 | 1992-12-10 | Logothetou Rella Helen | Utilisation d'inhibiteurs de proteases neutres activees par le calcium dans des preparations pharmaceutiques |
| GR1001044B (el) * | 1991-06-03 | 1993-04-28 | Logothetou Rella Eleni | Μηχανισμός διή?ησης νεοπλασματικών κυττάρων και η χρήση του αναστολέα της Ca2+ -εξαρτώμενης ουδέτερης πρωτεάσης για την παρασκευή φαρμακευτικών αντικαρκινικών συν?έσεων. |
| WO1998038990A1 (fr) * | 1997-03-07 | 1998-09-11 | Hoechst Marion Roussel, Inc. | Methode de traitement d'un trauma associe a des lesions du cerveau, de la moelle epiniere ou de nerfs peripheriques au moyen de carbobenzyloxy phenylalaninals di- et tri-pepetidiques n-proteges |
| FR2778851A1 (fr) * | 1998-05-19 | 1999-11-26 | Aetsrn | Composition a base d'inhibiteurs de cysteine-proteases pour retarder la senescence, l'autodestruction et l'hemolyse des erythrocytes |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990000401A3 (fr) | 1990-03-22 |
| GB8815962D0 (en) | 1988-08-10 |
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